1. Background of the Prior Art
The invention relates to methods and pharmaceutical compositions for treating diabetes mellitus and other insulin resistance syndromes.
2. Description of the Prior Art
Vanadium is a ubiquitous trace element found in very low concentrations in most living organisms, including human beings. Although it appears to be an essential nutritional element, its specific physiological role has not been conclusively defined. Over the past decade, the biological effects of vanadium have been sought. Vanadium inhibits the activity of various enzymes, particularly the ion transport ATPases, ribonuclease, acid phosphatase and alkaline phosphatase. The effects of vanadium on carbohydrate metabolism have been extensively examined, and vanadium has been found to have profound insulin-like effects.
Vanadium was discovered in 1830. It was used by Lyonnet and colleagues in an attempt to treat several diseases, and was found to decrease glycosuria in patients with diabetes. In the past decade, interest in vanadium was rekindled by the observations that vanadate has a number of insulin-like actions in vitro. These include stimulation of glucose transport into cells (both adipocytes and myocytes), glucose oxidation, glucose storage, glycogen synthesis, and lipogenesis; and inhibition of lipolysis. The effects are rapid and occur within 30 minutes. The actions of vanadium may be related to its ability to enhance phosphorylation of several enzymes and cellular proteins. These actions may be mediated by the stimulation of a vanadium activated cytosolic tyrosine kinase.
In vivo, oral administration of vanadate via drinking water has almost no effect on the glycemia of normal animals, but in diabetic animals causes a dramatic decline in blood glucose to normal or near normal levels without increasing plasma insulin levels. Depending on the studies, insulin levels are either unchanged or decreased. In contrast to the rapid in vitro effects, the in vivo effect is delayed, being seen over the course of several days. In addition to the sustained improvement of blood glucose, the in vivo effects of vanadium include augmentation of muscle and liver glucose uptake and storage, partial weight gain, and improved cardiac performance. The effects have been seen in streptozotocin induced diabetic rats, pancreatectomized diabetic rats, genetically diabetic db/db mice, and obese hyperinsulinemic fa/fa fatty rats.
For the in vivo studies heretofore disclosed in the literature, vanadium has generally been administered as a sodium salt, in the form of either sodium orthovanadate (Na.sub.3 VO.sub.4) or sodium metavanadate (NaVO.sub.3), with the vanadyl salt, vanadyl sulfate trihydrate, also used. These have been given to the test animals in drinking water or in chow. Several protocols describe using a progressively increasing concentration, since the animals appear to have an aversion to the taste of the vanadate salts. Relatively large doses of vanadate have been used since there is poor intestinal absorption of only 1.2%. Typical concentrations in the drinking water have been quite high, e.g., 0.2 to 0.6 mg/ml. It is noted that less sodium metavanadate is required than sodium orthovanadate, possibly because this salt provides 50% more vanadate on a weight basis.
Magnesium is a ubiquitous element in nature, forming 2.1% of the earth's crust. It is an essential nutritional element, the second most abundant intracellular cation in the human body, and has a key role in many metabolic functions. There are many clinical signs, symptoms and disease states attributable to altered magnesium homeostasis. Serum magnesium levels, which are those generally measured, reflect only 1% of the total body magnesium content. Yet, in one study, hypomagnesemia was found in 47% of serum specimens submitted for electrolyte analyses. Magnesium deficiency may be more likely to occur in diabetes mellitus as a consequence of polyuria.
Low levels of intracellular free magnesium have been found in both type II diabetes mellitus and in essential hypertension. Moreover, in patients with essential hypertension, intracellular free magnesium levels have been closely and inversely correlated with both systolic and diastolic blood pressure, and with the integrated plasma insulin response to oral glucose. These observations suggest that the clinical association of hypertension and peripheral insulin resistance (reduced insulin sensitivity) could, in part, be accounted for by magnesium deficiency. Oral magnesium supplementation has been shown to lower blood pressure both in patients with essential hypertension and in individuals with type II diabetes. Ongoing studies are evaluating whether oral magnesium supplementation in either type II diabetes or in essential hypertension is associated with an improvement in insulin sensitivity.
There are many magnesium supplements available in the marketplace, particularly magnesium chloride and magnesium oxide.
Rosetti et al. (Diabetes, 39:1243-50, 1990) studied the effects of lithium and vanadate on glucose metabolism in diabetic rats, and found that rats administered a combination of lithium, vanadate, magnesium and zinc had improved glucose disposal rates in comparison with control groups and groups receiving only lithium and vanadate.